In surgical and orthopedic treatments, prosthesis operations are often required for filling in defects or hollow portions of bone which may result from a fracture of bone or a surgical removal of a bone tumor. Also in the field of dental surgery, similar dental operations are often required for filling in spoiled void portions in maxilla or mandible resulting from pyorroea alveolaris. It has been a common practice to harvest bone from a donor site, for example from the iliac crest of the patient, to fill up the defect or hollow portion of bone and thereby to promote the regeneration of the bone tissue. However, to perform such an operation, normal, undamaged bone tissue must be taken up from an unspoiled portion. This operation causes additional pain to the patient and is, in addition, a very troublesome procedure. Moreover, when the volume of the defect or void in the patient's bone is large, the amount of bone obtainable from the patient's own body is not always adequate to fully fill in the defect or void. In such cases, it is inevitable to use a substitute for the patient's own bone tissue.
Even though the same sort of bone tissue has been used as the substitute, the implanted substitute may be rejected by the living tissue due to the foreign body rejection reaction (by the immune system). For these reasons, post-operation recovery of the defect is not always satisfactory. Accordingly, such an operation has not yet been recognized as fully satisfactory in practice.
In recent years, intensive studies have been made on artificial materials called biomaterials to be introduced in the human body for repairing damages therein. A variety of metal alloys and organic materials have been used as the substitute for the hard tissues in the living body. However, it has been recognized that these materials tend to dissolve or otherwise deteriorate in the environment of living tissue and that these materials are toxic to the living body and cause a so called foreign body rejection reaction. Ceramic materials have been used because of their excellent compatibility with the living body and because they are typically free of the aforementioned difficulties. Artificial bones and teeth have been developed from ceramic materials, particularly alumina, carbon or tricalcium phosphate or from sintered masses or single crystal of hydroxyapatite which have superior compatibility with the living body. These embodiments have attracted a good deal of public attention. However, the conventional ceramic materials have a disadvantage in that the bone formation activity or bone filling process is relatively slow.
An acceleration of this bone filling process can be achieved by the principle of osteoconduction if an empty space is filled with porous materials which serve as a scaffold for the newly formed bone [Reddi, H., Cytokine & Growth Factor Reviews 8 (1997) 11 to 20]. Alternatively, bone repair can be accelerated by osteoinduction, which involves the application of appropriate growth factors capable of differentiating mesenchymal stem cells to osteoblasts [Wozney, J. M. and Rosen, V., Clin Orthop Rel Res 346 (1998) 26 to 37].
The most useful growth factors in osteoinduction are bone morphogenetic proteins (BMPs), which are differentiation factors and have been isolated based on their ability to induce bone formation [Wozney, J. M., et al., Science 242 (1988) 1528 to 534]. They build a BMP family with more than thirty members belonging to a TGF-β-super-family. The BMP family is divided to subfamilies including the BMPs, such as BMP-2 and BMP-4, osteogenic proteins (OPs), such as OP-1 or BMP-7, OP-2 or BMP-8, BMP-5, BMP-6 or Vgr-1, cartilage-derived morphogenetic proteins (CDMPs), such as CDMP-1 or BMP-14 or GDF-5, growth/differentiation factors (GDFs), such as GDF-1, GDF-3, GDF-8, GDF-9, GDF-11 or BMP-11, GDF-12 and GDF-14, and other subfamilies, such as BMP-3 or osteogenin, BMP-9 or GDF-2, and BMP10 (Reddi et al., 1997, supra).
Especially in animal models, the BMPs have proved to be powerful inducers of bone formation and repair. However, due to the instant degradation of the BMPs upon contact with body fluids and the strong morphogenetic action of the BMPs, un-physiologically high doses of the BMPs are needed for the osteoinductive bioactivity [Weber, F. E., et al., Int J Oral Maxillofac Surg 31 (2002) 60 to 65; Rose, F. R. A. and Oreffo, R. O. C. Biochem Biophys Res Corn 292 (2002) 1 to 7]. Topical administration routes must be used, which makes the choice of the carrier system critical, and no suitable carrier systems are currently available. Since the BMPs are usually produced with recombinant techniques and thus are expensive and available only in limited amounts, the BMPs, despite the acknowledged effect, have had no impact on the medical treatment of patients and they are not clinically applied at present.